Paliperidone amino-acid ester and preparation method thereof[invention field]
The present invention relates to one and treat schizoid paliperidone compound and preparation method thereof, particularly relate to a kind of paliperidone carboxylate and preparation method thereof.
[background of invention]
Paliperidone (Formulae II) is benzisoxa oxazole derivatives, it is the antipsychotics of a new generation, for a kind of selectivity monoaminergic antagonist with peculiar property, very high avidity can be had with serotonin energy 5-HT2 acceptor and d2 dopamine receptor.Therefore, U.S. FDA ratifies oral controlled-release tablet (Invega) listing of being developed by Johson & Johnson in December, 2006, but the hydroxyl due to compound causes its wetting ability to increase, thus reduce its oral specific absorption, its absolute bioavailability is only 28%, cause its every daily dosage portion to increase, thus the side effect do not absorbed the drug making it possible increase.The long chain fatty acid ester of paliperidone also studies have reported that, but it is metabolized to the speed of paliperidone slowly in vivo, can not reach the effect for the treatment of very soon, and long-chain ester metabolic enzyme in human body and Difference of Metabolism, cause drug effectiveness otherness large.Paliperidone short-chain ester and ether research find, the fragment that its vivo degradation gets off may cause the toxicity in body, thus increases its toxicity.
Formulae II
Amino acid is needed by human material, and toxicity is lower.Some amino acid, as L-glutamic acid, are the major excitatory neurotransmitters in mammalian central nervous system, are also Major Nutrient materials in human body.
Have not yet to see the report be attached to by amino acid in paliperidone.
[summary of the invention]
For above paliperidone and compound thereof as the deficiency of antipsychotics, the invention provides one and be used for the treatment of schizoid paliperidone carboxylate and preparation method thereof.The amino acid of needed by human body and paliperidone are connected into Paliperidone amino-acid ester by the present invention, in vivo can fast degradation, and the paliperidone after degraded plays pharmacologically active, and the amino acid fragment of degraded is human body essential matter, and toxicity is lower.Connect amino acid whose Paliperidone amino-acid ester simultaneously and change its wetting ability, or promote that medicine small intestine site absorbs as the substrate of peptide transporter in body-1 (PEPT1), thus increase its oral administration biaavailability, reduce toxic side effect, increase curative effect.
Formula I R=AA
Paliperidone carboxylate of the present invention is the ester prodrug thereof become with amino acid whose carboxyl reaction by paliperidone, and the optical isomer of this compounds or its compound pharmaceutical salts all can be used for the related psychiatric conditions such as treatment schizophrenia.
Amino acid moiety preferably but be not limited to natural amino acid, i.e. D, L-type, comprises glycine, l-asparagine, glutamine, Serine, Threonine, halfcystine, L-Ala, α-amino-isovaleric acid, leucine, Isoleucine, phenylalanine, tryptophane, tyrosine, methionine(Met), proline(Pro), aspartic acid, L-glutamic acid, Methionin, Histidine, arginine, ornithine, methionine(Met), poly-lysine.
The Paliperidone amino-acid ester of the compounds of this invention (I) can use multiple method to prepare, and describes certain methods wherein of the present invention in detail, but do not mean that any limitation of the invention in following Examples scheme.
[embodiment]
Now further describe the present invention in conjunction with following Examples.
Embodiment 1: the synthesis (compound 1) of paliperidone glycinate
A. amino protection
Add in flask by L-glycine 0.75g (10mmol), add water 10ml, acetone 20ml, adds the triethylamine (Et of 2.08ml under stirring3n), control temperature adds tert-Butyl dicarbonate (Boc) under stirring at 25 DEG C2o4.27ml (20mmol), and continue to stir 4.5h, pressure reducing and steaming acetone, with ether, 3 times are extracted to water layer, each 10ml, after water layer is adjusted pH value to 2-3 with rare HC1, extraction into ethyl acetate 3 times, each 15ml, combined ethyl acetate layer, wash 2 times with saturated common salt, each 10ml, after anhydrous sodium sulfate drying, filter evaporate to dryness, the product ethyl acetate obtained and sherwood oil (1: 2, volume ratio) carry out crystallization, obtain Boc-L-glycine, yield is 90%.(yield: the ratio of the product production of actual production that input unit's quantity raw material obtains and the product production of Theoretical Calculation.)
B. the synthesis of ester:
The paliperidone of the glycine after the protection of 2.6mmol and 1.3mmol is dissolved in the anhydrous methylene chloride of 6.8ml; catalyzer DMAP (DMAP) and N; N '-dicyclohexylcarbodiimide (DCC) adds 10mmol (12.5ml) after dissolving with anhydrous methylene chloride under 0 degree; stir 3-5h with this understanding; at room temperature stir 48h, make paliperidone 9 hydroxyls and amino acid whose carboxyl generation esterification.Cross and filter filter residue, filtrate adds methylene chloride to 30ml, and the sodium carbonate solution with 5% washs 3 times, each 10ml, and then washes with water to neutrality.Anhydrous sodium sulfate drying, filter, filtrate boils off most of solvent.Neutral alumina column purification, wet method dress post, dry method loading, then uses ethyl acetate: ethanol=40: the eluent of 1 rinses.Obtain product, be spin-dried for solution, then dissolve with a small amount of anhydrous methylene chloride, put into plastic syringe and volatilize, then be put into abundant evaporate to dryness in round-bottomed flask.Yield is 70%.
C. deprotection
Add in the there-necked flask that agitator is housed 1.17g (2.0mmol) b walk synthesized by esterification products and 8mL methylene dichloride, abundant stirring makes it dissolve completely, then under 0 DEG C and continuous stirring, slowly drip trifluoroacetic acid 2mL (0.026mol), more slowly rise to the abundant stirring reaction 2h of room temperature.After having reacted, under reduced pressure boil off solvent, residuum water, methylene dichloride and 0.5ml concentrated ammonia solution dissolve, and separate organic layer after swaying, water layer dichloromethane extraction 3 times, each 20ml.Merge organic layer, fully wash with saturated sodium-chloride water solution, then use anhydrous Na2sO4dried overnight.Filter out siccative, after pressure reducing and steaming methylene dichloride, neutral alumina chromatography (eluent is ethyl acetate) is separated, and obtain final desired product, yield is 90%.
Embodiment 2: the synthesis (compound 2) of paliperidone DL-Alanine ester
A. amino protective reaction:
DL-Alanine 0.89g (10mmol) is added in flask, be dissolved in the water of 3.5ml and 1 of 7ml, 4-dioxane, frozen water cools, stir lower Isosorbide-5-Nitrae-dioxane (7ml) solution of dropping tert-Butyl dicarbonate 2.2ml (11mmol) and the aqueous solution (7ml) of sodium hydroxide (0.5g), dropwise, ice bath stirs 2h, stirred overnight at room temperature.The hydrochloric acid adding 1mol/l adjusts PH to 2, is extracted with ethyl acetate 3 times, merges, and use the hydrochloric acid of 1mol/l and water washing three times respectively, anhydrous sodium sulfate drying, boils off solvent, and sherwood oil recrystallization obtains white solid, and yield is 70%.
B. the synthesis of ester:
L-Ala after the protection of 3mmol is dissolved in the anhydrous methylene chloride of 20ml; add catalyzer DMAP; under agitation add the paliperidone of 3mmol; the DCC of 10mmol is added under-3 degree; stir 3-5h with this understanding; at room temperature stir and spend the night, make the upper hydroxyl of paliperidone 9 and amino acid whose carboxyl generation esterification.Cross and filter filter residue, filtrate concentrates rear dichloromethane extraction, and the sodium carbonate solution with 5% washs 2 times, washes with water to neutrality, uses saturated common salt water washing.Drying, boils off solvent, obtains product.Neutral alumina column purification, wet method dress post, dry method loading, then uses ethyl acetate: ethanol=60: the eluent of 1 rinses.Obtain product, be spin-dried for solution, then dissolve with a small amount of anhydrous methylene chloride, put into plastic syringe and volatilize, then be put into abundant evaporate to dryness in round-bottomed flask.Yield is 60%.
C. protection is sloughed
The esterification products synthesized by 1.19g (2mmol) b step and 8mL methylene dichloride is added in the there-necked flask that agitator is housed, abundant stirring makes it dissolve completely, then under 0 DEG C and continuous stirring, slowly drip trifluoroacetic acid 2mL (0.026mol), more slowly rise to the abundant stirring reaction 2h of room temperature.After having reacted, under reduced pressure boil off solvent, residuum water, methylene dichloride and 0.5ml concentrated ammonia solution dissolve, and separate organic layer after swaying, water layer dichloromethane extraction 3 times, each 20ml.Merge organic layer, fully wash with saturated sodium-chloride water solution, then use anhydrous Na2sO4dried overnight.Filter out siccative, after pressure reducing and steaming methylene dichloride, neutral alumina chromatography (eluent is ethyl acetate) is separated, and obtain final desired product, yield is 90%.
Embodiment 3: the synthesis (compound 3) of paliperidone D-Val ester
A. amino protection
Add in flask by D-Val (10mmol), add water 10ml, and acetone 20ml adds the Et of 2.08ml under stirring3n, control temperature adds (Boc) under stirring at 25 DEG C2o (10mmol, 2.2ml), and continue to stir 4.5h, pressure reducing and steaming acetone, extracts 3 times with ether to water layer, each 10ml, after water layer is adjusted pH value to 2-3 with rare HC1, extraction into ethyl acetate 3 times, each 15ml, merge organic layer, wash 2 times with saturated common salt, each 10ml, anhydrous Na2sO4after drying, filter evaporate to dryness, the product ethyl acetate obtained and sherwood oil (1: 2, volume ratio) carry out crystallization, and obtain Boc-D-α-amino-isovaleric acid, yield is 70%.
B. the synthesis of ester:
The paliperidone of the D-Val after the protection of 2.6mmol and 1.3mmol is dissolved in the anhydrous methylene chloride of 13.6ml; catalyzer DMAP and DCC adds 10mmol (2.5ml) after dissolving with anhydrous methylene chloride under 0 degree; stir 3-5h with this understanding; at room temperature stir 48h, make paliperidone 9 hydroxyls and amino acid whose carboxyl generation esterification.Cross and filter filter residue, filtrate adds methylene chloride to 30ml, and the sodium carbonate solution with 5% washs 3 times, and each 10ml is washed till neutrality with water 3 × 10ml.Anhydrous sodium sulfate drying, filter, filtrate boils off most of solvent.Neutral alumina column purification, wet method dress post, dry method loading, then uses ethyl acetate: ethanol=70: the eluent of 1 rinses.Obtain product, be spin-dried for solution, then use a small amount of anhydrous methylene chloride (1.5ml) molten, put into EP pipe and volatilize, then be put into abundant evaporate to dryness in round-bottomed flask.Yield is 70%.
C. deprotection
The esterification products synthesized by 1.25g (2.0mmol) step b and 8mL methylene dichloride is added in the there-necked flask that agitator is housed, abundant stirring makes it dissolve completely, then under 0 DEG C and continuous stirring, slowly drip trifluoroacetic acid 2mL (0.026mol), more slowly rise to the abundant stirring reaction 2h of room temperature.After having reacted, under reduced pressure boil off solvent, residuum water, methylene dichloride and 0.5ml concentrated ammonia solution dissolve, and separate organic layer after swaying, water layer dichloromethane extraction 3 times, each 20ml.Merge organic layer, fully wash with saturated sodium-chloride water solution, then use anhydrous Na2sO4dried overnight.Filter out siccative, after pressure reducing and steaming methylene dichloride, neutral alumina chromatography (eluent is ethyl acetate) is separated, and obtain final desired product, yield is 90%.
Embodiment 4: the synthesis (compound 4) of paliperidone Pidolidone ester
A. amino protection
Add in flask by Pidolidone (10mmol), add water 15ml, and acetone 15ml adds the Et of 2.08ml under stirring3n, control temperature adds (Boc) under stirring at 25 DEG C2o (20mmol, 4.27m), and continue to stir 4.5h, pressure reducing and steaming acetone, extracts 3 times with ether to water layer, each 10ml, after water layer is adjusted pH value to 2-3 with rare HC1, extraction into ethyl acetate 3 times, each 15ml, merge organic layer, wash 2 times with saturated common salt, each 10ml, after anhydrous Na 2SO4 drying, filter evaporate to dryness, the product ethyl acetate obtained and sherwood oil (1: 2, volume ratio) carry out crystallization, obtain Boc-L-L-glutamic acid, yield is 90%.
B. the synthesis of ester:
The paliperidone of the L-glutamic acid after the protection of 3.9mmol and 1.3mmol is dissolved in the anhydrous methylene chloride of 12ml; catalyzer DMAP and DCC adds 10mmol (12.5ml) after dissolving with anhydrous methylene chloride under 0 degree; stir 3-5h with this understanding; at room temperature stir 48h, make paliperidone 9 hydroxyls and amino acid whose carboxyl generation esterification.Cross and filter filter residue, filtrate adds methylene chloride to 30ml, and the sodium carbonate solution with 5% washs 3 times, and each 10ml, washes with water to neutrality.Anhydrous sodium sulfate drying, filter, filtrate boils off most of solvent.Neutral alumina column purification, wet method dress post, dry method loading, then uses ethyl acetate: ethanol=80: the eluent of 1 rinses.Obtain product, be spin-dried for solution, then use a small amount of anhydrous methylene chloride molten, put into EP pipe and volatilize, then be put into abundant evaporate to dryness in round-bottomed flask.Yield is 65%.
C. deprotection
Add in the there-necked flask that agitator is housed 1.31g (2.0mmol) b walk synthesized by esterification products and 8mL methylene dichloride, abundant stirring makes it dissolve completely, then under 0 DEG C and continuous stirring, slowly drip trifluoroacetic acid 2mL (0.026mol), more slowly rise to the abundant stirring reaction 2h of room temperature.After having reacted, under reduced pressure boil off solvent, residuum water, methylene dichloride and 0.5ml concentrated ammonia solution dissolve, and separate organic layer after swaying, water layer dichloromethane extraction 3 times, each 20ml.Merge organic layer, fully wash with saturated sodium-chloride water solution, then use anhydrous Na2sO4dried overnight.Filter out siccative, after pressure reducing and steaming methylene dichloride, neutral alumina chromatography (eluent is ethyl acetate) is separated, and obtain final desired product, yield is 85%.
Embodiment 5: the synthesis (compound 5) of paliperidone L-threonine ester
A. amino protection
Add in flask by L-threonine (10mmol), add water 10ml, and acetone 20ml adds the Et of 2.08ml under stirring3n, control temperature adds (Boc) under stirring at 25 DEG C2o (20mmol, 4.27m), and continue to stir 4.5h, pressure reducing and steaming acetone, extracts 3 times with ether to water layer, each 10ml, after water layer is adjusted pH value to 2-3 with rare HC1, extraction into ethyl acetate 3 times, each 15ml, merge organic layer, wash 2 times with saturated common salt, each 10ml, anhydrous Na2sO4after drying, filter evaporate to dryness, the product ethyl acetate obtained and sherwood oil (1: 2, volume ratio) carry out crystallization, and obtain Boc-L-Threonine, yield is 90%.
B. the synthesis of ester:
The paliperidone of the L-threonine after the protection of 2.6mmol and 1.3mmol is dissolved in the anhydrous methylene chloride of 7.5ml; catalyzer DMAP and DCC adds 10mmol (12.5ml) after dissolving with anhydrous methylene chloride under 0 degree; stir 3-5h with this understanding; at room temperature stir 48h, make paliperidone 9 hydroxyls and amino acid whose carboxyl generation esterification.Cross and filter filter residue, filtrate adds methylene chloride to 30ml, and the sodium carbonate solution with 5% washs 3 times, and each 10ml is washed till neutrality with water 3 × 10ml.Anhydrous sodium sulfate drying, filter, filtrate boils off most of solvent.Neutral alumina column purification, wet method dress post, dry method loading, then uses ethyl acetate: ethanol=90: the eluent of 1 rinses.Obtain product, be spin-dried for solution, then use a small amount of anhydrous methylene chloride molten, put into EP pipe and volatilize, then be put into abundant evaporate to dryness in round-bottomed flask.Yield is 65%.
C. deprotection
Add in the there-necked flask that agitator is housed 1.25g (2.0mmol) b walk synthesized by esterification products and 8mL methylene dichloride, abundant stirring makes it dissolve completely, then under 0 DEG C and continuous stirring, slowly drip trifluoroacetic acid 2mL (0.026mol), more slowly rise to the abundant stirring reaction 2h of room temperature.After having reacted, under reduced pressure boil off solvent, residuum water, methylene dichloride and 0.5ml concentrated ammonia solution dissolve, and separate organic layer after swaying, water layer dichloromethane extraction 3 times, each 20ml.Merge organic layer, fully wash with saturated sodium-chloride water solution, then use anhydrous Na2sO4 dried overnight.Filter out siccative, after pressure reducing and steaming methylene dichloride, neutral alumina chromatography (eluent: ethyl acetate) is separated, and obtain final desired product, yield is 85%.
Embodiment 6: the synthesis (compound 6) of paliperidone 1B ester
A. amino protection
Add in flask by 1B (10mmol), add water 15ml, and acetone 15ml adds the Et of 2.08ml under stirring3n, control temperature adds (Boc) under stirring at 25 DEG C2o (20mmol, 4.27m), and continue to stir 4.5h, pressure reducing and steaming acetone, extracts 3 times with ether to water layer, each 10ml, after water layer is adjusted pH value to 2-3 with rare HC1, extraction into ethyl acetate 3 times, each 15ml, merge organic layer, wash 2 times with saturated common salt, each 10ml, after anhydrous Na 2SO4 drying, filter evaporate to dryness, the product ethyl acetate obtained and sherwood oil (1: 2, volume ratio) carry out crystallization, obtain Boc-L-Methionin, yield is 90%.
B. the synthesis of ester:
The paliperidone of the 1B after the protection of 2.6mmol and 1.3mmol is dissolved in the anhydrous methylene chloride of 7.5ml; catalyzer DMAP and DCC adds 10mmol (12.5ml) after dissolving with anhydrous methylene chloride under 0 degree; stir 3-5h with this understanding; at room temperature stir 48h, make paliperidone 9 hydroxyls and amino acid whose carboxyl generation esterification.Cross and filter filter residue, filtrate adds methylene chloride to 30ml, and the sodium carbonate solution with 5% washs 3 times, and each 10ml is washed till neutrality with water 3 × 10ml.Anhydrous sodium sulfate drying, filter, filtrate boils off most of solvent.Neutral alumina column purification, wet method dress post, dry method loading, then uses ethyl acetate: ethanol=100: the eluent of 1 rinses.Obtain product, be spin-dried for solution, then use a small amount of anhydrous methylene chloride molten, put into EP pipe and volatilize, then be put into abundant evaporate to dryness in round-bottomed flask.Yield is 65%.
C. deprotection
Add in the there-necked flask that agitator is housed 1.31g (2.0mmol) b walk synthesized by esterification products and 8mL methylene dichloride, abundant stirring makes it dissolve completely, then under 0 DEG C and continuous stirring, slowly drip trifluoroacetic acid 2mL (0.026mol), more slowly rise to the abundant stirring reaction 2h of room temperature.After having reacted, under reduced pressure boil off solvent, residuum water, methylene dichloride and 0.5ml concentrated ammonia solution dissolve, and separate organic layer after swaying, water layer dichloromethane extraction 3 times, each 20ml.Merge organic layer, fully wash with saturated sodium-chloride water solution, then use anhydrous Na2sO4 dried overnight.Filter out siccative, after pressure reducing and steaming methylene dichloride, neutral alumina chromatography (eluent is ethyl acetate) is separated, and obtain final desired product, yield is 85%.
Embodiment 7: the synthesis of paliperidone glycine ester hydrochloride or acetate
A. amino protection
Add in flask by L-glycine 0.75g (10mmol), add water 10ml, and acetone 20ml adds the Et of 2.08ml under stirring3n, control temperature adds tert-Butyl dicarbonate (Boc) under stirring at 25 DEG C2o4.27ml, and continue to stir 4.5h, pressure reducing and steaming acetone, with ether, 3 times are extracted to water layer, each 10ml, after water layer is adjusted pH value to 2-3 with rare HC1, extraction into ethyl acetate 3 times, each 15ml, combined ethyl acetate layer, wash 2 times with saturated common salt, each 10ml, after anhydrous sodium sulfate drying, filter evaporate to dryness, the product ethyl acetate obtained and sherwood oil (1: 2, volume ratio) carry out crystallization, obtain Boc-L-glycine, yield is 90%.
B. the synthesis of ester:
The paliperidone of the glycine after the protection of 2.6mmol and 1.3mmol is dissolved in the anhydrous methylene chloride of 7.5ml; catalyzer DMAP and DCC adds 10mmol (12.5ml) after dissolving with anhydrous methylene chloride under 0 degree; stir 3-5h with this understanding; at room temperature stir 48h, make paliperidone 9 hydroxyls and amino acid whose carboxyl generation esterification.Cross and filter filter residue, filtrate adds methylene chloride to 30ml, and the sodium carbonate solution with 5% washs 3 times, each 10ml, and then washes with water to neutrality.Anhydrous sodium sulfate drying, filter, filtrate boils off most of solvent.Neutral alumina column purification, wet method dress post, dry method loading, then uses ethyl acetate: ethanol=40: the eluent of 1 rinses.Obtain product, be spin-dried for solution, then dissolve with a small amount of anhydrous methylene chloride, put into plastic syringe and volatilize, then be put into abundant evaporate to dryness in round-bottomed flask.Yield is 70%.
C. deprotection
Add in the there-necked flask that agitator is housed 1.17g (2.0mmol) b walk synthesized by esterification products and 8mL methylene dichloride, abundant stirring makes it dissolve completely, then under 0 DEG C and continuous stirring, slowly drip trifluoroacetic acid 2mL (0.026mol), more slowly rise to the abundant stirring reaction 2h of room temperature.After having reacted, under reduced pressure boil off solvent, residuum water, methylene dichloride and 0.5ml concentrated ammonia solution dissolve, and separate organic layer after swaying, water layer dichloromethane extraction 3 times, each 20ml.Merge organic layer, fully wash with saturated sodium-chloride water solution, then use anhydrous Na2sO4dried overnight.Filter out siccative, after pressure reducing and steaming methylene dichloride, resistates uses acetic acid ethyl dissolution again, then slowly drips the hydrogen chloride solution of ether or the acetum of ether, separates out white solid.Filter, with dehydrated alcohol-anhydrous diethyl ether mixed solvent recrystallization, can obtain paliperidone glycine ester hydrochloride or acetate light yellow crystal, product yield is 77.9%.
Embodiment 8, Paliperidone amino-acid ester hepatocyte metabolic rate measure
40 μ g Paliperidone amino-acid ester: compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, being dissolved in 0.01M respectively contains in the potassium phosphate buffer of 1mmolNADPH, with 25 μ l people liver cell S9 (20mg protein/ml, H961) mix, cultivate 2 hours at 37 DEG C, then with dense perchloric acid quench mix.Centrifugal remove the protein of precipitation after, supernatant solution strong phosphoric acid potassium solution adjustment pH=3, more centrifugal.Direct injection supernatant solution enters HPLC and analyzes.
Metabolic products is as shown in table 1 below, compound in liver cell metabolism in two hours to the metabolic rate of activeconstituents Paliperidone from 70% to 95% not etc., depend on different amino acid esters.
Table 1 compound metabolic rate of 2 hours in liver cell
Embodiment 9, Paliperidone amino-acid ester Bioavailability Determination
The beasle dog of 39 body weight about 10 kilograms is divided into 13 groups, by 9.4 μm of ol/ dogs by compound 1, and 2,3,4,5,6 carry out gavage, by the blood sampling of set time, survey the concentration of active metabolism compounds paliperidone and Paliperidone amino-acid ester in blood.The simultaneously beasle dog of control group 3 body weight about 10 kilograms, paliperidone by with mole intravenously administrable such as precursor compound, survey the concentration of paliperidone in blood.
It is active metabolite paliperidone that result Paliperidone amino-acid ester to enter after in beasle dog body almost all metabolism immediately through gi tract, and the concentration of protype compound is very low.The bioavailability of Paliperidone amino-acid ester medicine is apparently higher than 28% of paliperidone, and the especially precursor medicine of hydrophobicity Paliperidone amino-acid ester, bioavailability improves highly significant.
Embodiment 10, Paliperidone amino-acid ester LD50 measure
Get healthy kunming mice 130, body weight 18 ~ 22g, male and female half and half, often kind of tested material determines 5 dosage groups, each dosage 10 mouse in mortality ratio 0% (Dn) and 100% (Dm) scope.By randomly assigne grouping, weigh, mark, before gastric infusion, mouse food 12h, freely intakes.Close observation after administration, rises, observes 2 every day, Continuous Observation 14 days on the 2nd day.The reaction of detailed record animal and death condition, dead animal performs an autopsy on sb., the change of visual inspection internal organs.The mouse of death does not continue to observe, and comprises diet, moving situation, excretion situation, every physical signs of death time and dead front and back.
Table 2 Paliperidone amino-acid ester LD50 (medium lethal dose)
The LD50 of Paliperidone amino-acid ester is close to paliperidone or toxicity is similar, according to the acute toxicity grading criteria of China's compound, Paliperidone amino-acid ester and paliperidone mouse LD50 of passing through mouth are at 51 ~ 500mg/kg, toxic grade is 4 grades, belong to moderate toxicity, but in preparation, everyone (body weight 60kg meter) recommended dose every day of Paliperidone amino-acid ester is only 0.2mg ~ 20mg, and therefore security is higher.
The preparation of embodiment 11, oral sustained release capsule
Paliperidone amino-acid ester (5%), Microcrystalline Cellulose (90%), Vltra tears (5%) are mixed in ordinary fluidized bed and granulate.Then dressing is carried out with containing ethyl cellulose (80%) and Vltra tears (20%) mixing material, after dressing drying, the particle ball of dressing is loaded in hard gelatin capsule, every capsules pastille (calculating by paliperidone) 6mg, dressing degree is 5%.
The prolonged action preparation of embodiment 12, Paliperidone amino-acid ester
Because the moment Plasma Concentration of normal injection agent is higher, the toxicity therefore produced is comparatively large, simultaneously frequent drug administration, and the conformability of patient is declined, and therefore Paliperidone amino-acid ester is made prolonged action preparation by the present embodiment.
Continuous release microsphere preparation: the Paliperidone amino-acid ester according to synthesis is fat-soluble cpds, adopts O/W homogenizing emulsifying legal system for Paliperidone amino-acid ester PLGA microballoon.First take 7.5gPVA, join in 1.2L water gradually, induction stirring makes it dissolve, and adds water and is settled to 1.5L, obtains external phase, is used 1ml methylene dichloride (DCM) saturated.Then take a certain amount of Paliperidone amino-acid ester and PLGA respectively, be dissolved in DCM, make pastille disperse phase.Under emulsify at a high speed condition, be all expelled in polyvinyl alcohol (PVA) aqueous solution by disperse phase in 1min, emulsification 3min, gentle mechanical stirring 4h, volatilizees completely to DCM, obtains solidified microsphere.Collect the microballoon of solidification, cross 154 μm and 10 μm of millipore filtrations, repeatedly clean with deionized water, to wash away the medicine of residual PVA solution and non-balling-up.Finally all be transferred in cillin bottle by the microballoon after washing, lyophilize, obtains microsphere sample, is placed in 4 DEG C of refrigerator moisture eliminators and preserves.Carry out drug loading, encapsulation rate, size-grade distribution, Electronic Speculum and inside and outside releasing research.
Long-acting oily mixed suspension preparation: particulate Paliperidone amino-acid ester stable crystal form being prepared into a certain size, is then prepared into oil suspension with oil for injection (Viscotrol C, sesame wet goods) suspendible.
Temperature sensitive injected gel: Paliperidone amino-acid ester and part macromolecular material (as PLGA) are dissolved in N-Methyl pyrrolidone (NMP) or dimethyl sulfoxide (DMSO) (DMSO), are uniformly dispersed and are prepared into temperature sensitive temperature sensitive injected gel.
Long-acting implantation agent: Paliperidone amino-acid ester and mixing silicon rubber is even, adds certain linking agent and catalyzer mixes.
In the above-described embodiments, only to invention has been exemplary description, but those skilled in the art can carry out various amendment to the present invention without departing from the spirit and scope of the present invention after reading present patent application.